Paclitaxel (Taxol.RTM.), a diterpene taxane compound, is a natural product extracted from the bark of the Pacific yew tree, Taxus Brevifolia. It has been shown to have excellent antitumor activity in in vivo animal models, and recent studies have elucidated its unique mode of action, which involves abnormal polymerization of tubulin and disruption of mitosis during the cell cycle. Taxol has recently been approved for the treatment of refractory advanced ovarian cancer, breast cancer and most recently, AIDS-related Kaposi's Sarcoma. The results of paclitaxel clinical studies are replete in scientific periodicals and have been reviewed by numerous authors, such as Rowinsky and Donehower in The Clinical Pharmacology and Use of Antimicrotubule Agents in Cancer Chemotherapeutics, Pharmac. Ther., 52, pp. 35-84 (1991); Spencer and Faulds, Paclitaxel, A Review of its Pharmacodynamic and Pharmacokinetic Properties and Therapeutic Potential in the Treatment of Cancer, Drugs, 48 (5), pp. 794-847 (1994); K. C. Nicolau et al., Chemistry and Biology of Taxol, Angew. Chem., Int. Ed. Eng., 33, pp. 15-44 (1994); F. A. Holmes, A. P. Kudelka, J. J. Kavanaugh, M. H. Huber, J. A. Ajani, and V. Valero, "Taxane Anticancer Agents--Basic Science and Current Status", edited by Gunda I Georg, Thomas C. Chen, Iwao Ojima, and Dolotrai M. Vyas, pp. 31-57 American Chemical Society, Wash., D.C. (1995); Susan G. Arbuck and Barbara Blaylock, "Taxol.RTM. Science and Applications", edited by Matthew Suffness, pp. 379-416, CRC Press, Boca Raton, Fla. (1995) and the references cited therein.
Commercial pharmaceutical products containing paclitaxel are available, e.g. for the treatment of ovarian and breast cancer, and most recently, AIDS-related Kaposi's Sarcoma. Paclitaxel has also shown promising results in clinical studies for the treatment of other cancers. As a result, the demand for paclitaxel continues to escalate, and ever increasing amounts of paclitaxel are needed with each passing year for continued research and clinical studies. Paclitaxel is extracted with difficulty and in low yields for the bark of Taxus brevifolia (approximately 1 kg. of the drug is isolated from the bark of 3,000 T. brevifolia trees). Because of the difficulty in extracting adequate yields, alternative sources for synthesizing paclitaxel are needed.
10-deacetylbaccatin-III ("10-DAB") (1, Scheme-1) is currently the starting material for the semi-synthesis of paclitaxel, and may be readily extracted from the needles and twigs of the European Yew tree, Taxus baccata L. 10-DAB does not, however, exhibit the degree of anti-tumor activity demonstrated by paclitaxel. Accordingly, the semi-synthesis of paclitaxel from baccatin III. 10-DAB and other taxane compounds is of great interest and importance.
Three distinct approaches for making paclitaxel are known in the literature. Two approaches utilizes 7-O-TES-baccatin-III (3, Scheme-1) obtained from the selective silylation and acetylation of 10-DAB (1) (Greene et al., J. Am. Chem. Soc. 110, p. 5917 (1988). The first route, developed by Prof. Holton and disclosed in U.S. Pat. No. 5,274,124 (Scheme-2) reacts the lithium anion of 3 with a .beta.-lactam to introduce the required amino acid side chain at the 13-position. The second route developed by Bristol-Myers Squibb Co. and disclosed in U.S. patent application Ser. No. 07/995,443, and by D. G. I. Kingston et al. in Tetrahedron Letters 35, p. 4483 (1994), (Scheme-3) couples 3 with an oxazolinecarboxylic acid ((4S-trans)-4,5-dihydro-2,4-diphenyl-5-oxazolecarboxylic acid) (4) using DCC or similar dehydrating agent. Using DCC, A Commercon et al. at Rhone Poulenc Rhorer (Tetrahedron Letters 33, pp.5185-5188 (1992), have developed a third synthesis of paclitaxel coupling 7-O-Troc-baccatin-III (5) with the protected .beta.-phenylisoserine (6) shown in Scheme-4. ##STR1## ##STR2## ##STR3## ##STR4##